This invention relates to bicyclic compounds useful as glycoprotein IIb/IIIa antagonists for the prevention of thrombosis.
The most prevalent vascular disease states are related to platelet dependent narrowing of the blood supply such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls. Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex IIb/IIIa. When a platelet is activated by an agonist such as thrombin the GPIIb/IIIa binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation.
Heretofore it has been proposed to block these thrombus formation sites by the use of various therapeutic agents.
U.S. Pat. No. 5,064,814 teaches N-amidino-piperidine carboxyl cyclic amino acid derivatives as anti-thrombotic agents.
U.S. Pat. 5,039,805 teaches various benzoic acid and phenylacetic acid derivatives for the inhibition of the binding of fibrinogen to the fibrinogen receptor, glycoprotein IIb/IIIa.
Seven membered ring containing bicyclic compounds are taught to be fibrinogen antagonists in PCT International patent application WO 93/00095.
EP 456835 describes bicyclic compounds having fused six membered rings (quinazoline-3-alkanoic acid derivates) which are reported to have an inhibitory effect on platelet aggregation.
PCT International patent application WO 93/08174 describes nonpeptidyl integrin inhibitors which are bicyclic 6 and 7 membered fused ring systems which have therapeutic applications in diseases for which blocking platelet aggregation is indicated.
Patent Application WO94/12478 describes the preparation of 6,5-bicyclic compounds stated to be effective for inhibiting platelet aggregation.
Patent Application WO94/08962 describes the preparation of 6,5-bicyclic compounds stated to be effective for inhibiting platelet aggregation.
British Patent application GB 2276384 describes novel oxoquinazolin derivatives stated to have fibrinogen receptor antagonistic activity.
The article, xe2x80x9cFrom Peptide to Non-Peptide. 1. The Elucidation of a Bioactive Conformation of the arginine-glycine-aspartic Acid Recognition Sequencexe2x80x9d, by Robert S. McDowell, et. al., J. Am. Chem. Soc. 1994, 116, pp. 5069-5076, describes design of non-peptidal inhibitors of fibrinogen-glycoprotein IIb/IIIa binding.
The publication, xe2x80x9cChapter 9. Glycoprotein IIbIIIa Antagonistsxe2x80x9d by Brent K. Blackburn and Thomas R. Gadek, Annual Reports in Medicinal Chemistryxe2x80x9428, Section IIxe2x80x94Cardiovascular and Pulmonary Agents, pp 79-88, 1993, publ. by Academic Pres, Inc., describes non-peptides as antagonists of GPIIbIIIa/fibrinogen interaction.
The article, xe2x80x9cFrom Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-Peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione Scaffoldxe2x80x9d, by Robert S. McDowell, et. al., J. Am. Chem. Soc. 1994, 116, pp 5077-5083, describes benzodiazepinedione which are inhibitors of platelet aggregation.
Quinoline compounds have been recited in the patent literature for a variety of medicinal uses. For example, European Patent Application 0 315 399; U.S. Pat. No. 5,041,453; PCT Patent Application WO 89/04303, and PCT Patent Application WO 89/04304 describe quinoline derivatives useful as lipoxygenase inhibitors and/or leukotriene antagonists possessing anti-inflammatory and anti-allergic. properties. These compounds must contain three aromatic rings, each interrupted with oxygen, or sulfur, and possibly other groups.
There is a need in the area of cardiovascular and cerebrovascular therapeutics for alternative agents which can be used in the prevention and treatment of thrombi.
It is a discovery of this invention that certain novel bicyclic compounds block the GPIIb/IIIa fibrinogen receptor, thereby inhibiting platelet aggregation and subsequent thrombus formation. Pharmaceutical formulations containing the bicyclic compounds of this invention inhibit aggregation and are useful for the prophylaxis and treatment of thrombogenic diseases, such as myocardial infarction, angina, stroke, peripheral arterial disease, disseminated intravascular coagulation and venous thrombosis.
The present invention is a novel bicyclic compound having a nucleus formed from two fused six membered rings, A and B, represented by the formula (I), as hereinafter defined, and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof: 
Another aspect of the invention is a pharmaceutical formulation containing the novel bicyclic compounds of the invention.
Another aspect of the invention is a method of inhibiting platelet aggregation, inhibiting fibrinogen binding, or preventing thrombosis by administering to a mammal the bicyclic compounds of the invention.
Another aspect of this invention is a method of treating a human to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, and anastomosis of vascular grafts; wherein the method comprises administering to said human the novel bicyclic compound of this invention.
The term xe2x80x9calkylxe2x80x9d used herein refers to a monovalent straight or branched chain radical of from one to ten carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
The term, xe2x80x9chalosubstituted alkylxe2x80x9d as used herein refers to an alkyl group as just defined, substituted by one, two or three halogen atoms selected from fluorine, chlorine, bromine, and iodine. Examples of such groups include chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term, xe2x80x9carylxe2x80x9d, when used alone means a homocyclic aromatic radical whether or not fused. Preferred aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
The term, xe2x80x9csubstituted arylxe2x80x9d, denotes an aryl group substituted with one, two, or three substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C1-C10 alkyl, C1-C10 alkoxy, trifluoromethyl, amino, aminomethyl, and the like. Examples of such groups are 4-chlorophenyl, 2-methylphenyl, 3-methyl-4-hydroxyphenyl, and 3-ethoxyphenyl.
The term, xe2x80x9carylalkylxe2x80x9d, means one, two or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated. A typical arylalkyl group is the benzyl group.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
The term, xe2x80x9calkylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from one to ten carbon atoms, including but not limited to, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(C2H5)xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, and the like.
The term xe2x80x9calkenylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon double bond, including but not limited to, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH(CHxe2x95x90CH2)CH2, and the like.
The term, xe2x80x9calkynylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon triple bond, including but not limited to, 
and the like.
The term, xe2x80x9camidinoxe2x80x9d refers to the radical having the structural formula; 
The term, xe2x80x9cbasic radicalxe2x80x9d refers to an organic radical which is a proton acceptor. Illustrative basic radicals are amidino, piperidyl, guanidino, and amino.
The term, xe2x80x9cbasic groupxe2x80x9d refers to an organic group containing one or more basic radicals. A basic group may comprise only an basic radical.
The term, xe2x80x9cnon-interfering organic radicalxe2x80x9d is any organic substituent present on the bicyclic compound of formula (I) which is not deleterious to its efficacy as a Glycoprotein IIb/IIIa antagonist.
The term, xe2x80x9cacid radicalxe2x80x9d refers to an organic radical which is a proton donor. Illustrative acid radicals include; 
The term, xe2x80x9cacidic groupxe2x80x9d is an organic group containing one or more acid radicals. An acidic group may comprise only an acid radical.
Compounds of this invention have the general formula (I) shown below: 
and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof.
The bicyclic nucleus of (I) is formed from the fusion of two six membered rings xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9dhaving carbon bridging atoms. The dashed lines in the structural formula (I) signify the optional presence of an additional bond, that is, unsaturation that will lend aromatic character to the ring structure. It will be understood that the bridging carbon atoms will either be unsubstituted or substituted (with hydrogen) depending on the degree of unsaturation in the bicyclic ring system. The A ring atoms A1, A2, A3, and A4 and the B ring atoms B1, B2, B3, B4 of formula (I) are independently selected from carbon, oxygen, sulfur, and nitrogen, with the proviso that at least two of B1, B2, B3, B4 are carbon. More precisely, A1, A3, and A4 are independently selected from carbon, oxygen, sulfur, and nitrogen and A2 is independently selected from carbon or nitrogen, provided that A2 have an unsatisfied bond if A2 is N and provided that at least two of A1, A2, A3, and A4 are carbon. Correspondingly, B1, B2, and B4 are independently selected from carbon, oxygen, sulfur, and nitrogen and B3 is independently selected from carbon or nitrogen and provided that B3 have an unsatisfied bond if B3 is N and provided that at least two of B1, B2, B3 and B4 are carbon.
The bicyclic nuclei of the compounds of the invention may be formed from ring systems inclusive of, but not limited to, any of the nuclei (1 through 16) depicted below: 
The nuclei depicted by formulae (1) to (16) supra., and (17) to (30) infra., have the A and B ring atom numberings and corresponding substituent placements as shown in (1) above. For example, the nuclei (Imm) and (Ipp). 
would yield different products within the scope of formula (I).
Compounds of the invention corresponding to formula (I) with nuclei (1) to (19) are represented by the formulae (Ia) to (Ie) below: 
Other bicyclic nuclei suitable for forming the compounds of formula (I) are represented by the formulae (17) through (21a) below: 
Compounds of the invention corresponding to formula (I) with nuclei (17) to (21a) are represented by the formulae (If) through (Ijj) below: 
Bicyclic nuclei ring substituted with xe2x95x90O suitable for forming the compounds of formula (I) are represented by the formulae (22) through (27) below: 
Compounds of the invention corresponding to formula (I) with oxo substituted nuclei (22) to (27) are represented by the formulae (Ik) to (Im) below: 
Other bicyclic nuclei ring substituted with xe2x95x90O suitable for forming the compounds of formula (I) are represented by the formulae (28) through (30) below: 
Compounds of the invention corresponding to formula (I) with nuclei (28) to (30) are represented by the formulae (In) to (Ip) below: 
The most preferred nuclei for the compounds of this invention are isoquinoline, isoquinolone, naphthalene, tetrahydronapthalene, tetralone, dihydronaphthalene, and benzopyran.
The substituent R3 is an acidic group or a pharmaceutically acceptable salt or solvate thereof, (or a prodrug derivative of said acidic group) and preferably is an acidic group containing carboxyl functionality. The R3 group may be the sole substituent of ring atom B3. Alternatively, when the B3 atom can accept two bonds, these bonds may be satisfied by a double bond on the R3 group (with the R3 double bond attached directly to the B ring of formula I), or a second R3 group, or a second group selected from hydrogen, C1-C10 alkyl, C1-C10 halosubstituted alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, C7-C12 aralkyl, hydroxy, C1-C10 alkoxy, C1-C10 aralkoxy, carboxy, acyl, cyano, halo, nitro, and sulfo.
R3, the acidic group, is preferably selected from the group having members represented by the following formulae: 
The substituents R0 are non-interfering organic radicals and are the same or different on each atom B1, B2, and B4 and the same or different between atoms B1, B2, and B4 and are independently selected from hydrogen, C1-C10 alkyl, C1-C10 halosubstituted alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, C6-C12 arylalkyl, hydroxy, C1-C10 alkoxy, C6-C12 arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo; with the proviso that only one of B1, B2, and B4 may also be substituted with xe2x95x90O or xe2x95x90S.
The number, n, of R0 substituents attached to the atoms B1, B2, and B4 of the B ring is an integer from 0 to 6 and depends on the sum of the number of unsatisfied bonds present in the individual atoms B1, B2, and B4. Typically, n will be from 2 to 6 for most of the compounds of the invention. Thus, for example, where the B ring is saturated, B2 is oxygen, and B1 and B4 are carbon, then no R0 substituent will be present on atom B2 as shown in structural formula (Iq) below: 
For B rings having unsaturation, the number of unsatisfied bonds present in the individual atoms B1, B2, and B4 is decreased and the number of R0 substituents required is correspondingly less. Thus, for example, where the B ring is unsaturated, B2 is nitrogen, and B1 and B4 are carbon, then no R0 substituent will be present on B2 as shown in structural formula (Ir) below: 
The A ring atoms A1, A2, A3, and A4 are independently selected from carbon, oxygen, sulfur, and nitrogen, with the proviso that at least two of A1, A2, A3, and A4 are carbon.
The substituents R10 are the same or different on each atom A1, A3, and A4 and the same or different between atoms A1, A3 and A4, and are independently selected from hydrogen, C1-C10 alkyl, C1-C10 halosubstituted alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, C6-C12 arylalkyl, hydroxy, alkoxy, C6-C12 arylalkoxy, carboxy, acyl, cyano, halo, nitro, and sulfo; with the proviso that only one of A1, A3, and A4 may also be substituted with xe2x95x90O or xe2x95x90S when two sites are available for substitution on a single atom (viz., when one or more of the dashed lines in the A ring of Formula I are absent and an A atom is carbon).
The number, m, of R10 substituents attached to the atoms A1, A3, and A4 of the A ring is an integer from 0 to 6 and depends on the sum of the number of unsatisfied bonds present in the individual atoms A1, A3, and A4 in a manner analogous to the substitution of R0 groups on the B ring as describe d above. Typically, n will be from 2 to 6 for most of the compounds of the invention. The atom, A2, of the A ring is substituted by linking group xe2x80x94(L)xe2x80x94 alone when A2 has only one unsatisfied bond, however, when A2 has two unsatisfied bonds the second bond may be satisfied by a group selected from hydrogen, alkyl, halosubstituted C1-C10 alkyl, C2C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, C7-C12 arylalkyl, hydroxy, C1-C10 alkoxy, C7-C12 arylalkoxy, acyl, cyano, halo, nitro, sulfo, and a basic group.
The linking group xe2x80x94(L)xe2x80x94 attached to the A2 atom of the A ring and is (i) a bond, or (ii) a divalent substituted or unsubstituted chain of from 1 to 10 atoms (viz., there are 1 to 10 atoms in the chain between the linking divalent bonds, with all other atoms pendent from these chain atoms). For example, when xe2x80x94(L)xe2x80x94 is a bond the compound of the invention may have the structural formula Is as follows: 
Alternatively, when xe2x80x94(L)xe2x80x94 is the linking group 
the compound of the invention may have the structural formula (It) as follows: 
Alkylene, alkenylene and alkynylene groups are suitable as linking groups. Preferred linking groups have 1 to 4 chain atoms and correspond to the general formulae: 
where Z1, Z2, Z3, and Z4 are atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen. Linking groups containing three chain atoms such as, 
where R is hydrogen or alkyl, may be used.
Particularly preferred are linking groups containing two chain atoms such as; 
The linking group; 
has cis and trans forms and both such forms and their mixtures in all proportions are within this invention.
Asymmetric linkers, for example, the linkers 
may be reversed in their point of attachment between the nucleus A ring and the basic group Q, as depicted in formulae (Iu) and (Iv) below: 
The substituent Q of formula (I) is a basic group. A basic group contains one or more basic radicals, Q1. Suitable basic radicals contain one or more nitrogen atoms and include amino, imino, amidino, N-alkylamidines, N,Nxe2x80x2-dialkyamidines, N-arylamidines, aminomethyleneamino, iminomethylamino, guanidino, aminoguanidino, alkylamino, dialkylamino, trialkylamino, alkylideneamino, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, amide, thioamide, benzamidino, pteridinyl, 4aH-carbozolyl, carbozolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, or any of the preceding substituted with amino, imino, amidino, aminomethyleneamino, iminomethylamino, guanidino, alkylamino, dialkylamino, trialkylamino, tetrahydroisoquinoline, dihydrosioindole, alkylideneamino groups or a group represented by the formula; 
Preferred basic radicals are selected from amino, piperidyl, guanidino, and amidino. The most preferred basic radicals are amidino and piperidyl represented by the formulae; 
The basic group Q may have the form of a basic radical (such as Q1 on formula Iw, infra.) pendant on a cyclic ring. Thus, Q, the basic group, may comprise two parts, namely, (i) one or more basic radicals, Q1and (ii) a cyclic group, xe2x80x9cDxe2x80x9d, having from 5 to 8 ring atoms. The D ring attached to the A2 atom of the A ring of the bicyclic nucleus throuth the linking group xe2x80x94(L)xe2x80x94 as shown in formula (I), supra. The D ring may also have substituents R20 which are selected from chlorine, fluorine or non-interfering organic radicals. The R20 substituents may be t in number, where t is an integer from zero to the number of unsatisfied bonds in the D ring. The basic radical Q1 attaches to the D ring in the manner shown in formula (Iw) below: 
Suitable D rings are formed from a nucleus selected from the group consisting of; benzene, cycloheptadiene, cycloheptatriene, cycloheptane, cyclohexane, cyclohexene, cyclohexadiene, cycloheptene, cyclooctadiene, cyclooctane, cyclooctatetraene, cyclooctene, cyclopentane, cyclopentene, imidazole, isooxazole, morpholine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydropyrimidine, 1H-tetrazole, thiazolidine, thiazole, thiopyran, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, dihydrofuran, dihydropyran, dioxane, dioxepin, dioxolane, furan, oxocane, tetrahydrofuran, tetrahydropyran, thiophene, and tetrahydrothiophene.
General formula (Ix) for the preferred compounds of the invention having a basic radical attached to a cyclic ring of 5 to 8 atoms is shown below: 
wherein;
A1, A3, A4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
A2 is independently selected from carbon or nitrogen, provided that A2 have an unsatisfied bond if A2 is N and provided that at least two of A1, A2, A3, and A4 are carbon;
B1, B2, B4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
B3 is independently selected from carbon or nitrogen, provided that B3 have an unsatisfied bond if B3 is N and provided that at least two of B1, B2, B3, B4 are carbon;
R3 is an acidic group containing one or more acid radicals;
n is a number from 0 to 6;
R0 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S; with the proviso that if R0 is xe2x95x90O or xe2x95x90S, then only one of B1, B2, B3, and B4 may be nitrogen;
m is a number from 0 to 6;
R10 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, and xe2x95x90S; with the proviso that only one R10 may be xe2x95x90O or xe2x95x90S;
t is a number from 0 to 3;
R20 is the same or different and is independently selected from hydrogen, halogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, carboxy, acyl, cyano, halo, nitro, sulfo;
linking group xe2x80x94(L)xe2x80x94 is a bond or a divalent substituted or unsubstituted chain of from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen; and;
D is a ring formed from 5 to 8 ring atoms and said ring atoms are independently selected from carbon, nitrogen, oxygen, or sulfur, with the proviso that at least two D ring atoms are carbon;
w is an integer from 1 to 3;
Q1 is a basic radical.
Compounds of the invention having A, B, and D rings are represented by the following formulae (Iy) to (Iah) below: 
A preferred basic group Q has a six membered D ring as represented by formula (Iai) below; 
where p is an integer from 0 to 8, as for example, the specific Q groups: 
A preferred embodiment of the compound of the invention is represented by formula II, below: 
In formula II the basic group on atom A2 of the nucleus has two parts, namely, (i) a six membered ring, D, which attaches to linking group xe2x80x94(L)xe2x80x94, and (ii) basic radical(s), Q1, (where w is an integer from 1 to 3) attached to the D ring. The basic radicals are as previously defined.
Atoms D2, D3, D4, D5 and D6 are independently selected from carbon, nitrogen, oxygen, or sulfur and atom D1 is selected from carbon or nitrogen; with the proviso that at least two of D1, D2, D3, D4, D5 and D6 are carbon. Q1 is a basic radical as previously defined. Preferred ring structures having pendant Q1 are those where atoms D1, D2, D3, D4, D5 and D6 form a cyclic ring selected from the group consisting of benzene, pyridine, piperidine, 1,2-piperazine, 1,3-piperazine, 1,4-piperazine, pyran, thiopyran, thiabenzene, cyclohexene, and cyclohexane, with benzene being the most preferred.
A preferred basic radical Q1 is an amidino radical.
The substituents R20 are the same or different on each atom D2, D3, D5, and D6 and the same or different between atoms D2, D3, D5, and D6 and are non-interfering organic radicals independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, and sulfo. The number, p, of substituents R20 is an integer from 0 to 8 depending on the sum of the number of unsatisfied bonds present in the individual atoms D2, D3, D5, and D6.
Preferred compounds of this invention are based on benzamidine substituted isoquinoline, isoquinolone, naphthalene, tetrahydronaphthalene, dihydronaphthalene, benzopyran, and tetralone nuclei, as partially illustrated in formulae (III) through (IIIe) below: 
where xe2x80x94(L)xe2x80x94, n, m, p, R0, R3, R10 and R20 are as previously defined. Most preferred are compounds where R10 and R20 are hydrogen and xe2x80x94(L)xe2x80x94 has 2 carbon atoms.
Another preferred aspect of the invention is where the D ring is contains one or more (preferably 1 or 2) substituents independently selected from chlorine or fluorine. The chlorine and fluorine substituents may be added to any 5 to 8 membered D ring described above. Illustrative compounds of the invention with substitution of six membered D rings are shown in formulae (IV) to (IVb) below: 
Without being bound by any theory of operation it is believed that the electron withdrawing groups such as fluorine reduce the basicity of the basic group and enhance the oral bioavailability of the compounds of the invention.
Specific compounds of the invention of the isoquinoline type which are highly preferred are represented by the following structural formulae (V) to (Vv) or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof: 
and mixtures of compounds (V) to (Vv).
Other specific compounds of the invention of the naphthalene/tetralin-type which are highly preferred are represented by the following structural formulae (VI) to (VIp) or pharmaceutically acceptable salts, solvates or prodrug derivatives thereof: 
and mixtures of compounds (VI) through (VIp).
Other preferred specific compounds of the invention are represented by the following structural formulae (L) to LXIII) and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof: 
and mixtures of any of (L) to (LXIII)
Other specific compounds of the invention of the benzopyran-type which are highly preferred are represented by the following structural formulae (VIII) to (VIIIi) or a pharmaceutically acceptable salt, solvate or prodrug derivatives thereof: 
Other compounds of the invention having a bicyclic nucleus with an A ring oxygen atom are represented for the following formulae (IX) to (IX1) below: 
The compounds of the invention possess at least one acidic functional substituent (viz., R3 of Formula I) and, as such, are capable of forming salts. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an anion exchange resin on the salt cycle.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine actions, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et. al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)).
The basic portion of the compounds of the invention (viz., group Q of formula I and group Q1 of formula II) may be reacted with suitable organic or inorganic acids to form salts of the invention. Representative salts include those selected from the group comprising; acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, chloride, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanllate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
The compounds of the formula (I) can also be in the form of zwitterions, since they contain both acidic and basic functionality and are capable of self-protonation.
Certain compounds of the invention possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
Prodrugs are derivatives of the compounds of the invention which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. For example, ester derivatives of compounds of this invention are often active in vivo, but not in vitro. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine. Simple aliphatic or aromatic esters derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
Preferred are the C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention (per formula I). Particularly preferred are the C1-C4 alkyl esters, for example, where the R3 acidic group has been esterified to form a group represented by one of the following formulae: 
Other specific prodrug derivatives which are compounds of the invention are represented by the formulae (Xa) and (xb) shown below: 
Acylated basic radicals which are part of basic group on the compounds of the invention have been found to significantly enhance bioavailability. Without being bound by any theory of operation, it is believed that lowering the basicity of basic group (Q) makes the compounds of this invention less subject to xe2x80x9cfood effectxe2x80x9d, that is, they have good availability in therapeutic administration to an animal without fasting.
Compounds of this invention may beneficially be dual prodrug derivatives. For example, the acidic group (R3) may be reacted to form an ester and the basic group Q (or basic radical Q1) may additionally be reacted to form an acylated basic derivative. Moreover, the prodrug derivatives of the compounds of this invention may be combined with other features herein taught to enhance bioavailability, for example, substitution of fluorine atoms on the D ring of the compounds of formula (II). These combined features result in a compound such as represented by the formula (Xc): 
Another highly preferred class of prodrugs of the invention are those formed by acylating the basic radicals (e.g., Q1) present on the compounds of the invention. The acyl portion of the acylated basic radical has the general formula: 
where R is C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl; and X is a bond, C, O, S, or N. Preferably R is C1-C4 alkyl and X is oxygen. For example, acylated basic radical prodrugs of the invention are prepared and illustrated in A, B, C, and D below:
A) acylation of amidine results in a prodrug derivative group: 
B) acylation of a cyclic amine such as piperidine results in a prodrug derivative group: 
C) acylation of guanidine results in a prodrug derivative group: 
D) acylation of a primary amine results in a prodrug derivative group: 
where, for A, B, C, and D above, R is as defined above for the acylated portion of the basic group.
The therapeutic compounds of this invention include prodrug derivatives of bicyclic compounds having a nucleus formed from two fused six membered rings, A and B, represented by the formula (Xd): 
wherein;
A1, A3, A4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
A2 is independently selected from carbon or nitrogen, provided that A2 have an unsatisfied bond if A2 is N and provided that at least two of A1, A2, A3, and A4 are carbon;
B1, B2, B4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
B3 is independently selected from carbon or nitrogen, provided that B3 have an unsatisfied bond if B3 is N and provided that at least two of B1, B2, B3, B4 are carbon;
n is a number from 2 to 6;
R0 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S; with the proviso that if R0 is xe2x95x900 or xe2x95x90S, then only one of B1, B2, B3, and B4 may be nitrogen;
m is a number from 2 to 6;
R10 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, and xe2x95x90S; with the proviso that only one R10 may be xe2x95x90O or xe2x95x90S;
linking group xe2x80x94(L)xe2x80x94 is a bond or a divalent substituted or unsubstituted chain of from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen; and;
Q2 is selected from (i) a basic group, or (ii) a basic group containing an acylated basic radical;
R13 is selected from (i) an acidic group containing an acid radical, or (ii) an acidic group containing an ester derivative of an acid radical;
provided that at Q2 is a basic group containing an acylated basic radical or R13 is an acidic group containing an ester derivative of an acid radical.
A preferred form of prodrug derivative is a compound of formula (Xd) having dual prodrug functionality, that is, where Q2 is a basic group containing an acylated basic radical and R13 is an acidic group containing an ester derivative of an acid radical.
Another preferred form of prodrug is a compound of formula (Xd) wherein the acylated portion of the acylated basic radical has the general formula: 
where R is C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl; and X is a bond, C, O, S, or N. Preferably R is C1-C4 alkyl and X is oxygen.
The group Q2 may comprise two parts, namely, (i) one or more radicals selected from basic radicals or acylated basic radicals each designated, xe2x80x9cQ3xe2x80x9d, and (ii) a cyclic group D (as previously defined form formula Iw). zzz
A general formula for the prodrug derivatives of this invention is a bicyclic compound having a nucleus formed from two fused six membered rings, A and B, represented by the formula (Xe), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof: 
wherein;
A1, A3, A4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
A2 is independently selected from carbon or nitrogen, provided that A2 have an unsatisfied bond if A2 is N and provided that at least two of A1, A2, A3, and A4 are carbon;
B1, B2, B4 are independently selected from carbon, oxygen, sulfur, and nitrogen;
B3 is independently selected from carbon or nitrogen, provided that B3 have an unsatisfied bond if B3 is N and provided that at least two of B1, B2, B3, B4 are carbon;
n is a number from 0 to 6;
R0 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S; with the proviso that if R0 is xe2x95x90O or xe2x95x90S, then only one of B1, B2, B3, and B4 may be nitrogen;
m is a number from 0 to 6;
R10 is the same or different and is independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, and xe2x95x90S; with the proviso that only one R10 may be xe2x95x90O or xe2x95x90S;
t is a number from 0 to 3;
R20 is the same or different and is independently selected from hydrogen, halogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, aralkoxy, carboxy, acyl, cyano, halo, nitro, sulfo;
linking group xe2x80x94(L)xe2x80x94 is a bond or a divalent substituted or unsubstituted chain of from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen; and;
D is a ring formed from 5 to 8 ring atoms and said ring atoms are independently selected from carbon, nitrogen, oxygen, or sulfur, with the proviso that at least two D ring atoms are carbon;
w is an integer from 1 to 3;
Q3 is selected from (i) a basic radical, or (ii) an acylated basic radical;
R13 is selected from (i) an acidic group containing an acid radical, or (ii) an acidic group containing an ester derivative of an acid radical;
provided that Q3 is an acylated basic radical or R13 is an acidic group containing an ester derivative of an acid radical;
The integer w is preferably 1.
It is preferred in formula (Xe) that R20 be chlorine and/or fluorine and t equal 1 or 2. Also preferred are compounds of formula (Xe) wherein Q3 is an acylated basic radical and R13 is an acidic group containing an ester derivative of an acid radical.
The most preferred acylated basic groups are carbamic acid esters of amidine, piperidine, or guanidine basic radicals. Carbamate acid C1 to C4 alkyl esters of amidine radicals are most highly preferred.
Carbamate ester prodrug derivatives of the invention may be prepared by a method such as shown in Scheme 27.
Preferred prodrug derivatives of the compounds of the invention having various features discused in this section are represented by the formulae (Xf) to (Xr) below: 
where, R=xe2x80x94H, xe2x80x94OMe, xe2x80x94OEt, xe2x80x94OPr
X=xe2x80x94Cl, xe2x80x94F, xe2x80x94H,
R15=Me, Et, Pr.
General synthesis schemes 1 through 33, infra., are used to prepare the compounds of the invention.
The following abbreviations are used throughout the synthesis Schemes and Examples:
The reactions described in the reaction schemes are carried out using standard chemical methodologies described and referenced in standard textbooks. Starting materials are commercially available reagents and reactions are carried out in standard laboratory glassware under reaction conditions of standard temperature and pressure, except where otherwise indicated. 
Scheme 1 teaches a method of preparing 2,6-disubstituted isoquinolones having an ether linked arginine isostere at C6 and an acetic acid residue at position 2. In the first step of Scheme 1, isoquinolone (1) reacts with benzyl bromide in the presence of potassium carbonate in refluxing acetone to give a benzyl protected phenol (2). This compound reacts with sodium hydride and is then alkylated on nitrogen with either alpha-bromo tert-butyl acetate or alpha-bromo methyl acetate to give a 2-substituted isoquinolone (3a) (6-benzyloxy-3,4-dihydro-1-oxo-2(1H)isoquinolone acetic acid-1, -dimethylethyl ester) or (3b). The C6 benzyl group is subsequently removed with hydrogen and palladium and subsequent alkylation of the 6-hydroxy group is accomplished with K2CO3 and alkyl bromide to give the di-substituted isoquinolone (5). Compound (5) is then transformed into the Boc protected amidine (6) using a series of reactions, namely; (i) reacting the nitrile with H2S, (ii) alkylating the intermediate thioamide with methyl iodide, (iii) reacting the intermediate thioimidate with ammonium acetate, and (iv) thereafter Boc protecting the formed amidine to give compound (6). Compound (6) is deprotected with neat TFA giving (7) as the TFA salt. 
Scheme 2 describes a synthesis method suitable to give carbon substitution at position C6 of the bicyclic nucleus. In this scheme compound (4) (6-hydroxy-3,4-dihydro-1-oxo-2(1H)isoquinolone acetic acid-1,1-dimethylethyl ester) from Scheme 1 is transformed into the triflate (8) using triflic anhydride and pyridine. The compound is thereafter reacted with the acetylenic compound (9a) or (9b) in the presence of palladium to give acetylene linked benzonitrile (10a) or (10b). Compound (10a) or (10b) is transformed again with the same set of procedures used to transform compound (5) (6-[(4 cyanophenyl) methoxy]-3,4-dihydro-1-oxo-2(1H)isoquinolone acetic acid, -1,1-dimethyl ethyl ester) to compound (6) (6-[[4-(1,1 dimethyl ethoxy carbonyl aminoiminomethyl)phenyl]methoxy]-3,4-dihydro-1-oxo-2(1H)isoquinolone acetic acid-1,1-dimethyl ethyl ester) to yield the amidine product (11a) or (11b). Compounds (11a) or (11b) may also be deprotected again with TFA to give compound (12a) or (12b). Alternatively, intermediate (10a) or (10b) can be either partially or fully hydrogenated as shown in the scheme giving the alkylene or alkenylene linked compound (13a) or (13b). Compound (13a) or (13b) is again transformed using the nitrile to amidine conversion previously described (Scheme 1, steps 5 greater than 6), giving compound (14a) or (14b) which is subsequently deprotected with TFA to give compound (15a) or (15b). 
Scheme 3 describes the preparation of isoquinolones containing nitrogen substitution at C6. This scheme starts with triflate (8) whose preparation was previously described in Scheme 2. The triflate is transformed to aryl ester (16) via the use of palladium, carbon monoxide and methanol. The ester (16) is then saponified with lithium hydroxide in aqueous THF. The free acid (7) is then subjected to a Curtius rearrangement (viz., formation of an isocyanate by thermal decomposition of acyl azides). The required acyl azide is formed with a triphenyl phosphoryl azide and then pyrolized in situ to give an isocyanate which is then trapped with benzyl alcohol giving Cbz protected aniline (18).
CBz-Aniline (18) is then transformed into free amine (19) with catalytic hydrogenation. Amine (19) is then acylated with paracyanobenzoic acid in the presence of EDCI and DMAP giving the amide-linked compound (20). Compound (20) is then transformed into the Boc protected amidine (21) again using the conditions of Scheme 1 and that compound is then deprotected with TFA to give compound (22). 
Scheme 4 describes how to make 2,6-disubstituted isoquinilones in which the 2-position is substituted with an aspartic acid moiety. Scheme 4 starts with compound (3b) whose preparation is described in Scheme 1. Compound (3b) is deprotonated with LHMDS and the resulting anion is quenched with alpha-bromo-t-butyl acetate to give compound (23). The 6-benzyl group of compound (23) is removed with palladium and hydrogen to give the free phenol (24). Compound (24) is then alkylated as described for the preparation of compound (5) in Scheme 1. The methyl ester (25) is then saponified with lithium hydroxide in THF to give the free carboxylate (26). The free carboxylate is then coupled with a variety of amines in the presence of EDCI and DMAP to give the half amide esters (27a) thru (27e). The half amide esters (27a) thru (27e) are then transformed again using the same protocol as previously described in Scheme 1 (steps 5-6)to give the Boc protected amidines (28a) thru (28e). The Boc protected amidine is then deprotected with TFA to give compounds (29a) thru (29e). 
Scheme 5 describes the preparation of 2,6-di-substituted isoquinilones in which the 2-position is substituted by an aspartate isostere. Scheme 5 compounds differ from the compounds prepared in Scheme 4 in that the R group of the Scheme 5 compound (36) does not contain an amide linkage like the Scheme 4 compounds (29a) thru (29e). Compound (2), the starting material, is prepared by the method of Scheme 1, then acylated with a variety of activated acids (acid halides or anhydrides) to give the corresponding imides (30a) thru (30e). Thereafter the imide is selectively reduced at its exocyclic carbonyl with DIBAH and then entrapped with acidic methanol to give alpha-methoxy amides (31a) thru (31e). Alternatively, alpha-methoxy amides (31) can be prepared by reacting the sodium salt of (2) with an appropriate alpha chloro ether (37). All of the alpha-methoxy amides (31a) thru (31g) are reacted with boron trifluoride etherate in the presence of a ketene acetal to give the beta,beta-di-substituted propionates (32a) through (32g). Thereafter, the benzyl group is removed from the 6 position by catalytic hydrogenation and phenols can be alkylated again in the same manner as shown in Scheme 1 (steps 4 greater than 5) to give the ether linked nitrites (34a) to (34g). That nitrile can then be converted to the Boc protected amidine (35a) to (35g) as shown in Scheme 1 (steps 5 greater than 6), Thereafter, deprotection gives the final compounds (36a) to (36g). 
Scheme 6 describes the preparation of compounds of the invention having a tetralin nucleus. 6-methoxy-2-tetralone (38) is reacted with tert-butyl diethylphosphono acetate to give unsaturated ester (39). Subsequent hydrogenation removes the unsaturation to give compound (40). Compound (40) is treated with boron tribromide and the crude product is reesterified with HCl and ethanol to give (41). The phenol (41) is then alkylated in the same manner as shown in Scheme 1 (step 4-5) giving (42). The nitrile can then be converted to the Boc protected amidine (43) as shown in Scheme 1 (step 5-6). The amidino ester (43) is then saponified with sodium hydroxide to give compound (44), which then is later deprotected with TFA and anisole to give the final product (45). 
Scheme 7 describes the preparation of compounds of the invention having a guanidine group as the basic functionality. Phenol (4), prepared in scheme 1, is alkylated with bromide (51) (prepared from the dibromide and potassium pthalimide) giving adduct (46). This compound is deprotected with aqueous hydrazine giving amine (47). Compound (47) is transformed into protected guanidine (49) with N,Nxe2x80x2-bis(tert-butoxy carbonyl)-S-methyl-isothiourea. Compound (49) is deprotected with TFA giving product (50) as the trifluoroacetate salt. 
Scheme 8 describes the preparation of compounds of the invention having an amine group as the basic functionality.
Compound (33a), prepared in scheme 5, is coupled with alcohol (51) (prepared from 3-(4-pyridyl)-propanol using standard protocols) using triphenyl phosphene and diethyl azodicarboxylate giving compound (52). Compound (52) is deprotected with neat TFA giving product (53) as the TFA salt. 
Scheme 9 describes the preparation of 2-6 disubstituted tetralins in which the 2 position is occupied by an a-alkoxyacetic acid residue and the 6 position retains either an ether linked benzamidine or an ether linked 4-alkylpiperidine moiety. The scheme begins with 6-methoxy-2-tetralone (60) which is sequentially treated with NaBH4 and then with DIBAH giving dihydoxy compound 62. The phenolic hydroxyl can be selectively alkylated with either xcex1-bromo-p-tolunitrile or the appropriate 4-alkylpiperidine giving compounds 63 and 67 respectively. Both compounds are then alkylated with tert-butyl bromoacetate under phase transfer conditions providing 64 and 68. Nitrile 64 is converted to the Boc protected amidine 65 and then to product 66 using the same sequence of reactions described in Scheme 1. Compound 68 is converted to the fully deprotected 69 by treatment with TFA. 
Scheme 10 outlines the preparation of 2,6-disubstituted tetralins in which an xcex1-aminoacetic acid moiety resides at position 2 and an ether linked 4-alkylpiperidiene emanates from position 6. Alchohol 67, prepared in Scheme 9, is oxidized with DMSO and TFAA using the conditions of Swern giving ketone 70 which is reductively aminated with glycine tert-butyl ester giving 71. This material is then deprotected with TFA giving 72. 
Scheme 11 outlines the preparation of 2,6-disubstituted tetralins in which the 2 position retains an xcex1-aminoacetic acid residue and the 6 position is occupied by an ether linked benzamidine. The synthesis starts with alcohol 63 (Scheme 9) which is oxidized with TFAA and DMSO (method of Swern) giving ketone 73. This material is then reductively aminated with glycine tert-butyl ester giving 74. The secondary nitrogen is then either Boc protected (76) or acylated (75). The Boc derivative is then transformed into protected amidine 77 using the same sequence of reactions outlined in Scheme 1. The material is then fully deprotected with TFA giving 78. In a like manner, the acetyl derivative 75 is transformed into 80. 
Scheme 12 outlines the preparation of tetralins having an acetic acid residue at C2 and an amide linked benzamidine at C6. In the first step, tetralone 81 is reduced with NaBH4 and the resultant unstable alcohol is dehydrated with TsOH in benzene giving dihydronapthalene 82. Osymylation of 82 affords diol 83 which is then subjected to the action of TsOH in refluxing benzene. The unstable 2-tetralone thus formed is not isolated but rather allowed to react with the sodium salt of tert-butyl diethylphosphonoacetate giving unsaturated ester 84 as a mixture of olefin isomers. This material is subjected to hydrogenation over palladium which effects saturation of the olefin and removal of the CBz group providing aniline 85. Acylation of 85 with 4-cyanobenzoic acid is accomplished with the aid of EDCI and the resulting amide 86 is transformed into the Boc protected amidine 87 using conditions previously described in Scheme 1. Removal of the Boc moiety and cleavage of the tert-butyl ester is accomplished with TFA giving 88. 
Scheme 13 describes the preparation of tetralin derivatives in which position 2 is substituted with an a-alkoxyacetic acid moiety and position 6 is substituted by an amide linked benzamidine. In this scheme, compound 82 from Scheme 12 is allowed to react with NaH and benzylbromide giving tertiary carbamate 88. This material is then subjected to osmylation and dehydration in the same manner as described for compound 83 in Scheme 12. The formed unstable 2-tetralone is immediately reduced to alcohol 90 with NaBH4. This material is alkylated with tert-butyl bromoacetate under phase transfer conditions resulting in ether 91. Catalytic hydrogenation liberates the 6-amino moiety (92) which is acylated with 4-cyanobenzoic acid in the presence of EDCI giving 93. Nitrile 93 is transformed into Boc protected amidine 94 using the series of transformations described in Scheme 1. Simultaneous deprotection of the amidine and acid moieties is accomplished with TFA giving final product 95. 
Scheme 14 outlines the synthesis of tetralones bearing an acetic acid moiety at position 2 and either an amide linked benzamidine or amide linked 4-alkylpiperidine at position 6. The scheme starts with tetralone 96 which is allowed to react with glyoxylic acid in the presence of NaOH yielding condensation product 97. The unsaturated ester 97 is reduced with Zn in HOAC and the resulting compound is transformed into aniline 98 by first removing the acetate with 6N HCl and then esterifying the acid moiety with ethanolic HCl. This material is then acylated with 4-cyanobenzoic acid via the agency of EDCI giving 99. The nitrile moiety of 99 is converted to Boc protected amidine 100 using the series of reactions described in Scheme 1. Saponification of the ester moiety with NaOH followed by treatment with TFA gives 102.
Compounds containing an amide linked 4-alkylpiperdine can be prepared by acylating aniline 98 with 103 giving analog 104. Saponification of ester 104 followed by TFA deprotection of the piperidine gives 106. 
Scheme 15 teaches a method of preparing tetralone derivatives in which position 2 is occupied by an unsaturated acid and position 6 is substituted by either an amide linked benzamidine or a 4-akylpiperidine. In the first step, compound 97 (scheme 14) can be is converted to aniline 107 by removing the acetate with 6N HCl and subsequent esterification with ethanolic HCl. This material can then be acylated with either 4-cyanobenzoic acid or the appropriate 4-alkylpiperidine (103). In the former case, the nitrile 111 can be transformed into amidine 112 using the same sequence of reactions described in Scheme 1. Saponification of 112 followed by treatment with TFA should yield 114. Piperidine adduct 108 can be subjected to saponification and TFA deprotection providing 110 in a similar manner. 
Scheme 16 describes the preparation of dihydronapthalene derivatives containing an acetic acid moiety at position 2 and an amide linked benzamidine at position 6. Tetralone 100 (Scheme 14) is allowed to react with NaBH4 in ethanol giving unstable alcohol 115. This material is treated with TsOH in THF giving dehydrated product 116. Ester saponification followed by deblocking the amidine with TFA gives the desired product 118. 
Scheme 17 outlines the general preparation of 2,6-disubstituted tetralones in which the 2 position is substituted with an acetic acid residue and the 6 position contains an amide-linked halogen-substituted benzamidine. Aniline 98 (prepared in Scheme 14) is allowed to react with benzoic acid 119 (prepared from 4-amino-2-fluoro-toluene using standard methods) in the presence of EDCI and DMAP. The resulting amide (120) is transformed into Boc protected amidine 121 using the same procedures outlined in Scheme 1. The ester moiety is then hydrolyzed giving acid 122 and then treatment with TFA provides compound 123. 
Scheme 18 teaches a method of preparing 2,6-disubstituted napthalenes having an acetic acid residue at position 2 and an ether linked arginine isostere at position 6. In the first step of Scheme 18, bromonapthalene 124 is subjected to transmetalation with t-BuLi and the resulting anion is quenched with ethyl oxalate. The resulting adduct 125 is then reduced with NaBH4 and the formed alcohol is acylated with acetic anhydride. Catalytic hydrogenation removes the benzilic acetate and liberates the 6-hydroxy moiety giving compound 126. The free phenol is then alkylated with xcex1-bromo-p-tolunitrile in the presence of K2CO3 giving disubstituted naphthalene 127. The nitrile moiety is then transformed into the Boc protected amidine 128 using the same sequence of reactions previously described in Scheme 1.
Saponification of the ester in 128 followed by removal of the Boc group with TFA gives final compound 130. 
Scheme 19 describes the preparation of disubstituted tetrahydroisoquinoline derivatives bearing an acetic acid moiety at position 2 and either an ether linked benzamidine or 4-alkyl piperidine moiety at position 6. The initial isoquinoline nucleus is prepared by LiAlH4 reduction of benzyl protected isoquinolone 2 (Scheme 1). This material was processed by either Boc protection giving compound 131 or alkylated with tert-butyl bromoacetate resulting in the formation of 132. The Boc protected material was subjected to hydrogenation which liberated the C6 phenol which was then alkylated with xcex1-bromotolunitrile giving adduct 137. The Boc group of this compound was cleaved with TFA and the resulting amine was then alkylated with tert-butyl bromoacetate giving compound 138. This compound was transformed into the Boc protected amidine 139 and then to the deprotected variant 140 using the procedures outlined in Scheme 1. The N-alkylated compound 132 was similarly subjected to hydrogenation and the resulting phenol was alkylated with the appropriate 4-alkylpiperidine giving 134. This material was deprotected with TFA giving 135. 
Scheme 20 teaches how to prepare 2,6-disubstituted tetrahydroisoquinoline derivatives bearing an acetic acid residue at position 2 and an amide linked benzamidine at position 6. The synthesis begins with acidic hydrolysis of the 6-acetamido group of isoquinolone 141 giving aniline 142. The crude material is then subjected to the action of benzyl bromide and K2CO3 in CH3CN giving a mixture of mono and di-benzyl protected isoquinolones. This mixture is subjected to LiAlH4 reduction forming the tetrahydroisoquinoline which is immediately treated with di-tert-butyl dicarbonate. The formed Boc protected material is then hydrogenated over palladium providing aniline 143. This material is acylated with p-cyanobenzoic acid giving 144. Treatment of this material with TFA gives the secondary amine which is alkylated with tert-butyl bromoacetate providing 145. Conversion of 145 to the Boc protected amidine 146 and then to its deprotected congener 147 is accomplished using the same procedures as outlined in Scheme 1. 
Scheme 21 describes a synthesis method suitable for the formation of 2,6-disubstituted tetralins containing a propionate or propenoate moiety at position 2 and an amide linked benzamidine at position 6. In the first step, nitro ester 148 is reduced with LiBH4 and the resultant alcohol is protected as its TBS ether. Compound 149 is then subjected to hydrogenation and the formed aniline is immediately treated with EDCI and p-cyanobenzoic acid giving amide 150. The silyl group of 150 is removed and the derived alcohol is subjected to oxidation with DMSO and oxalyl chloride (method of Swern). The aldehyde thus formed is not purified, rather it is allowed to react with the sodium salt of t-butyl diethylphosphonoacetate which yields a separable mixture of 151 (cis) and 152 (trans) olefin isomers. The trans isomer 152 is converted to the Boc protected amidine and then to deprotected compound 155 using the sequence described in Scheme 1. The cis isomer is subjected to hydrogenation over palladium to give saturated analog 153. This material is also converted to the Boc protected amidine and then to its deprotected congener 154 as described in Scheme 1. 
Scheme 22 describes a synthesis method for disubstituted tetralins bearing an xcex1-alkoxyacetic acid residue at C2 and a C6 carboxyl linked benzamidine. This scheme begins with 6-bromo-2-tetralone (156) which is reduced with NaBH4 and the resultant alcohol protected as its tert-butyldimethylsilyl (TBS) ether giving 157. Treatment of this compound with t-BuLi effects halogen metal exchange and the formed anion is quenched with CO2. The resulting carboxylate is immediately transformed into the benzyl ester with benzyl alcohol and EDCI. The TBS group is removed during workup with TBAF affording alcohol 158. The free secondary hydroxyl is alkylated with tert-butyl bromoacetate using phase transfer conditions and the 6-carboxylate is liberated via catalytic hydrogenation affording 159. Amide 160 is the result of allowing 159 to react with 4-cyanoaniline in the presence of EDCI and DMAP. Nitrile 160 is converted to the BOC protected amidine and thereafter to the fully deprotected 161 using conditions outlined in Scheme 1. 
Scheme 23 outlines the preparation of tetralins having an acetic acid residue at C2 and a C6 carboxyl linked benzamidine. In the first step, bromotetralone 156 is treated with ethylene glycol and TsOH under dehydrating conditions giving ketal 162. This material is treated with tBuLi and the resulting anion is quenched with CO2. The formed acid is immediately esterified with benzyl alcohol and EDCI giving 163. The spiro ketal contained in 163 is cleaved with aqueous HCl in acetone and the formed ketone is allowed to react with the sodium salt of tert butyl diethylphosphonoacetate giving 164 as a mixture of olefin isomers. Catalytic hydrogenation over Pd removes the unsaturation and liberates the C6 carboxylate giving acid 165. Condensation of this compound with 4-aminobenzonitrile gives amide 166. Conversion of 166 to Boc protected amidine 167 and then to final compound 168 is accomplished using the same sequence outlined in Scheme 1. 
Scheme 24 describes the preparation of 3,7-disubstituted benzopyrans in which the 3-position is substituted with an xcex1-alkoxyacetic acid moiety and the 7 position is substituted with an amide linked benzamidine. The synthesis begins with the allyl substituted aromatic 169. Acetamide hydrolysis is effected with NaOH in EtOH (Claisens alkali) and the resulting aniline is re-protected as its CBz counterpart. The free phenol is then acylated with acetic anhydride giving 170. The olefin is reacted with MCPBA giving the corresponding epoxide which is rearranged in the presence of NaI giving a mixture of 3-hydroxy and 3-acetoxy benzopyrans. This mixture is treated with LiOH giving alcohol 171. The alcohol moiety of 171 is then converted to its TBS ether and the resulting compound is alkylated on nitrogen to give fully protected 172. Liberation of the C3 hydroxy with TBAF followed by alkylation with tert-butyl bromoacetate under phase transfer condition gives 173. Catalytic hydrogenation provides aniline 174 which is acylated with 4-cyanobenzoic acid, providing amide 175. This material is first converted to the corresponding protected benzamidine 176 and then to its deblocked congener 177 using the same sequence of events outlined in Scheme 1. 
Scheme 25 outlines the preparation of 2,6-disubstituted tetralones in which the 2 position is substituted by an acetic acid moiety and the 6 position is substituted by either an alkoxy-linked benzamidine or alkoxy-linked 4-alkylpiperidine. In the first step, tetralone 178 is treated with NaOH and glyoxylic acid giving adduct 179. This material is reduced with Zn in acetic acid and the resulting acid (180) is reacted with diphenyldiazomethane giving benzhydryl ester 181. The free phenol can then be alkylated with xcex1-bromo-p-tolunitrile to give 184 or with the appropriate 4-alkylpiperdine giving 182. Nitrile 184 is then converted to the corresponding Boc protected amidine 185 and then to the fully deprotected compound 186 using the same sequence of reaction outlined in Scheme 1. Compound 182 is deprotected with TFA giving compound 183. 
Scheme 26 teaches a method to prepare tetrahydroisoquinolins in which the 2-position is substituted by an oxamic acid residue and the 6-position contains an ether linked benzamidine. In the first step, isoquinolone 2 is treated with LiAlH4 and the resulting product of reduction is acylated with methyl oxalylchloride giving compound 187. This material is subjected to hydrogenation and the resulting phenol is alkylated with either xcex1-bromotolunitrile or the appropriate 4-alkylpiperidine giving compounds 191 and 189 respectively. The nitrile moiety of 191 is transformed into Boc protected amidine 192 using the same procedures described in scheme 1. This material is then saponified with NaOH and the resulting acid is treated with TFA giving 193. Compound 190 is prepared using a similar saponification deprotection sequence. 
Scheme 27 describes the acylation of the amidine moiety contained in 2,6-disubstituted tetralones 365 and 366 which are prepared from compounds 102 and 123 (Scheme 14 and 17 respectively) by esterification with ethanol. The acylation is accomplished by reacting the benzamidine containing compound with an alkyl chloroformate in the presence of aqueous base, thus forming the derivatives 367 to 370. These materials can then be subjected to saponification with ethanolic NaOH yielding the free acid (see 371 in Scheme 27). 
The procedure of Scheme 27 is general and has also been applied to compounds containing an isoquinolone nucleus as shown in Scheme 28. In a like manner, one can also prepare N-acylated derivatives of benzamidine containing tetrahydroisoquinolins or benzopyrans. 
Scheme 29 describes the preparation of 2,6-disubstituted tetralones in which the 2-position is occupied by an acetic acid residue and the 6-position maintains an amide linked 4-propenoyl piperidine moiety. In the first step, alcohol 384 (prepared form 4-pyridylcarbinol by hydrogenation and protection) is oxidized with oxalyl chloride and DMSO giving the corresponding aldehyde. This material is not characterized but rather, reacted crude with the sodium salt of triethyl phosphonoacetate which gives the desired unsaturated ester 385. This material is saponified with LiOH and the resulting acid 386 is activated with oxalyl chloride giving 387. Aniline 98 reacts with acid chloride 387 giving adduct 388. This compound is N-deprotected with TFA giving ester 389 after salt exchange with HCl. Alternatively, saponification with LiOH first gives the free acid 390 which can then be N-deprotected with TFA providing 391. 
Scheme 30 teaches the preparation of 2,6 disubstituted tetrahydroisoquinolines bearing an acetic acid residue at position 2 and an amide linked 4-propenoyl piperidine at position 6. In the first step, the 6-amino moiety of 133 is acylated with acid chloride 387 (Scheme 29) giving adduct 392. This material can be fully deprotected with TFA providing 393. 
Scheme 31 outlines the preparation of 2,6-disubstituted tetralones in which the 2 position is occupied by an acetic acid moiety and the 6 position supports an amide-linked difluoro benzamidine. In the first step, difluoro benzonitrile 394 is lithiated with n-butyl lithium and the resulting anion is quenched with CO2 giving acid 395. This compound is then treated with oxalyl chloride and the resulting acid chloride 396 is reacted with aniline 98 giving adduct 397. The nitrile moiety in 397 is transformed into Boc protected amidine 398 using the same sequence of reactions employed for conversion of 5 to 6 as described in Scheme 1. Compound 398 can be deprotected with TFA providing 399. Alternatively, 398 can be fully deprotected by first cleaving the ester moiety with NaOH and then deprotecting the amidine with TFA yielding 400. 
Scheme 32 describes the preparation of 2,6-disubstituted tetralones bearing an acetic acid moiety at position 2 and an amide-linked amidino pyridine at position 6. In the first step, pyridine 401 is reacted with Et3N, TMSCl, and NaCN giving acid 402. This material is coupled with aniline 98 giving adduct 403. The nitrile in 403 is then reacted with the sodium salt of methane thiol giving the methylthioimidate. This intermediate is reacted with ammonium iodide providing an amidine which is BOC protected giving 404. Compound 404 is first reacted with ethanolic NaOH to cleave the ester and then with TFA to deprotect the amidine providing the fully deprotected congener 405. 
Scheme 33 describes the preparation of 2,6-disubstituted tetralones in which the amide-linked amidine contains a thiophene nucleus. In the first step, thiophene 406 is metalated with LDA and the resulting anion is quenched with CO2 giving acid 407. This acid is reacted with compound 98 in the presence of EDCI giving amide 408. The nitrile moiety in 408 is converted to a Boc protected amidine 409 using the same sequence of reactions used for the formation of compound 6 in Scheme 1. The resulting compound is first saponified with ethanolic NaOH and then N-deprotected with TFA giving compound 410 as the TFA salt. 
Scheme 34 teaches the preparation of 2,6 disubstituted benzopyrans in which the 2 position retains an acetic acid moiety and the 6 position contains an amide-linked fluoro-substituted benzamidine. In the first transformation, the nitro group is reduced with ammonium formate and palladium and the resulting aniline is Boc protected. The B ring unsaturation is then removed with Pd/C giving lactone 202. This material is reduced with DIBAH giving an intermediate lactol which is reacted with ethoxycarbonylmethylene triphenylphosphorane giving benzopyran 204. This material is then N-deprotected with TFA and the resulting aniline reacted with the acid chloride derived from fluoro-acid 119 giving adduct 307. This material was then subjected to the action of HCl in ethanol giving the intermediate imino-ether which was not characterized but instead reacted with ammonia resulting in the formation of 304. This material was then hydrolyzed with NaOH in ethanol giving the desired free acid 308 after neutralization.